This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Maternal cigarette smoking has been associated with a variety of adverse fetal, infant, and childhood developmental outcomes. In the United States alone, approximately one million infants are exposed prenatally to cigarette smoke each year! Although maternal cigarette smoking during pregnancy is a well documented risk factor for low birth weight, with its attendant complications for infant/childhood development, a direct linkage between prenatal cigarette smoke exposure and postnatal neurobehavioral/cognitive impairment remains poorly defined. In many cases, cognitive or behavioral dysfunction in children of mothers who smoked during pregnancy has been attributed to the clinical antecedent of low birthweight. However, emerging evidence indicates that exposure to cigarette smoke, or components such as nicotine and carbon monoxide, during pregnancy, affects the structural, molecular and/or functional development of the central nervous system at doses well below those at which perinatal growth alterations are elicited. This suggests that the magnitude of the problem regarding maternal smoking-induced neurobehavioral/cognitive impairment in children may be greatly underappreciated, and may extend well beyond only smoke-exposed low birthweight offspring. The global objective of the present research program is to establish mouse-human experimental correlates to mechanistically investigate the neuroanatomical, cellular and molecular substrates underlying maternal cigarette smoking-induced defects in neuro/cognitive development. Since the hippocampus subserves a central role [unreadable]across species [unreadable] in neuro/cognition, especially in the information processing involved in learning and memory, the central hypothesis under investigation is that maternal tobacco use during pregnancy interferes with the cellular and molecular ontogenesis of the hippocampus, resulting in altered hippocampus-dependent learning and memory in the offspring. Four Specific Aims are proposed to determine whether: 1] Tobacco smoke exposure during development, in a murine model simulating human active cigarette smoking, results in neurobehavioral abnormalities involving hippocampus-dependent learning and memory;2] Alterations in the establishment of normal cytoarchitecture and neurogenesis in the murine hippocampus are elicited by exposure to tobacco smoke during development, in the absence of attendant effects on murine fetal/neonatal growth;3] Tobacco smoke exposure during development results in hippocampal neuronal subtype-specific alterations in the expression of genes during murine ontogenesis that are critical mediators of neuronal developmental plasticity, learning and memory;4] Maternal smoking during pregnancy in humans results in adverse neurophysiological and neurobehavioral outcomes in infants, which are associated with alterations in hippocampus-dependent basic perceptual skills known to place the infant at risk for learning disabilities during childhood. Successful completion of the proposed studies will aid in understanding the effects of, and mechanisms underlying, in utero tobacco smoke exposure on neuro/cognitive development in infants and children, and [unreadable]long-term [unreadable] will facilitate the diagnosis of, and intervention into, learning disabilities and other cognitive impairments in children affected by prenatal maternal tobacco abuse.